Certain 3-pyridyl carbamate and 3-pyridyl-urea derivatives of dodecahydro-5,9-methanobenzocyclooctenes



Patented Mar. 3, 1970 3,498,993 of the pharmacological profile of the compounds of this CERTAIN 3 PYRIDYL CARBAMATE AND 3 PYR invention are tabulated below:

IDYL-UREA DERIVATIVES F DODECAHYDRO- 5,9-METHANOBENZOCYCLO0CTENES Edward J. Merrill, Whippany, N.J., assignor to Warner- 5 1 Lambert Pharmaceutical Company, Morris Plains, NJ a corporation of Delaware M; ,x- No Drawing. Continuation-impart of application Ser. No. g m

401,978, Oct. 6, 1964. This application Oct. 24, 1967, Ser. No. 678,162 R Int. Cl. C0711 31/40 3 US. Cl. 260-2955 2 Claims LDau Effective ABSTRACT OF THE DISCLOSURE f -g gs; Substituted dodecahydro-5,9'methanobenzocyclooctenes R2 R3 X (mg/kg) (mg/kg) of the Formula I CH3 CH3 on o 1 1, 000 30 CH3 OH; OH 0 2 1, 000 CH3 H OH 0 25 CH3 H 0 10 1 CH3 8-pyridyl OH 0 1 1, 000 0 20 CH3 CH@ H NH 1 20 CH3 3pyndyl H NH 1 400 5 CH3 3-pyridyl H NH 1 s00 15 *Based on reversal of ventricular arrhythmias to a normal sinus rhythm 6 5 4 using the coronary ligation technique of Harris and Kokernot, Am. J. Physiol. 163 505 (1950).

Generally speaking, a dose of about 300 to 500 mg.

wherein R R R and X are as defined below. These may be administered orally or by injection to a mamcompounds are useful as anti-arrhythmic agents. malian host weighing about 70 kg. in treating cardiac arrhythmia. The dosage requirements may be adjusted according to variation in body weight and variation in in- This application is a continuation-in-part application of dividual requirements according to methods known to the my co-pending application, Ser. No. 401,978, filed Oct. healing arts. Among the dosage forms which the com- 6, 1964, now abandoned. pounds of this invention may be administered are for This invention relates to compositions of matter and example, tablets, capsules, injectables, and the like. more particularly this invention relates to substituted do- These dosage forms are compounded according to the decahydro 5,9 methanobenzocyclooctenes having the pharmacists art with inert pharmaceutical carriers such structural formula: as lactose, water, terra alba, and the like.

it. 10 u 2 8 I 2 ll I la c j 3 H(R N-C) -x am n-( 29 x 6 5 R3 4 U n 6 5 L 0 II ,I wherein R represents hydrogen, lower alkyl of 1 to 6 These compounds may be administered either alone or carbons such as methyl, ethyl, propyl, isopropyl, etc., in combination with other known therapeutic agents which pentamethylene, phenyl or aralkyl such as phenyl lower will enhance their therapeutic spectrum such as tranalkyl; R represents hydrogen, lower alkyl of 1 to 6 carquilizers and sedatives, for example, chlordiazepoxide, bons such as methyl, ethyl, propyl, isopropyl, etc., phenyl phenobarbital; coronary vasodilators such as pentaenthyor aralkyl such as phenyl lower alkyl; R, is hydrogen or ritol tetranitrate; diuretics such as chlorothiazide, and the hydroxy and n is an integer of l or 2, and X is oxygen like. (-0-) or NH. The symbols R R and m as used According to this invention the above compounds are hereinafter have the same meaning as defined. produced by reacting a compound of the formula:

This invention also includes within its scope a novel process for the production of the above compounds as well as intermediates obtained during their synthesis.

The compounds of this invention exhibit potent antiarrhythmic activity and because of this activity they are 5 useful in the treatment of cardiac arrthythmia in mammals.

The compounds of this invention have an oral LD be- A tween 400 rug/kg. to greater than 1000 mg./kg. in mice. 33 The ED using the Harris et al. technique for measuring anti-arrythmic activity described in Am. J. Physiol 163 505 (1950), is between 5 to 30 mg./kg. in dogs. Examples with a reducing agent such as sodium or potassium boro- The reduction may be elfected at ice bath temperature such as to C. The starting compound A is prepared according to a procedure described by Barbulescu, Rev. Chim. (Bucharest) 7, 45 (1956) CA. 51, 3740 (1957). Briefly, cyclohexanone in alcohol is treated with an aldehyde of the formula R CHO at about 85 C. to obtain this starting material.

Compound B may then be treated with R -isocyanate, in an anhydrous solvent such as dry benzene, toluene or xylene at a temperature of 20 to 30 C. Compound B, if reacted with one mol of the R -isocyanate yields the desired compound of this invention wherein n is 1, whereas reacting with two mols or greater of R -isocyanate produces the desired compound wherein n is 2.

EXAMPLE 1 Dodecahydro-5,9-methano-l O-methylbenzocycloocten- 4a,11-diol 11- (N-methylcarbamate) To a vigorously stirred solution of 22.4 g. (0.1 mol) dodecahydro-5,9-methano methylbenzocycloocten- 4a,1l-diol in 500 cc. dry benzene is added a solution of 5.53 g. (0.1 mol) methyl isocyanate in 270 cc. dry benzene over 30 minutes. The solution is stirred at to C. for 18-24 hours then refluxed for five hours. The solvent is stripped and the residual oil is triturated with cc. petroleum ether, cooled and the solid filtered. This is recrystallized from 50% aqueous EtOH to give 16.3 g. (58%) of dodecahydro-5,9-methano-10-methylbenzocycloocten-4a,11-diol ll-(N-methylcarbamate) as a colorless solid melting at 124126 C. IR (Nnjol) 3580, 3250, 1710, 1685, 1560, 1260, 1140, 1000.

Analysis-Calm. for C H NO C, 68.30; H, 9.67; N, 4.99. Found: C, 68.58; H, 9.82; N, 4.95.

EXAMPLE 2 Dodecahydro-5,9-methano-IO-methylbenzocycloocten- 4a, 1 1-diol(2,5-dimethylallophinate To a magnetically stirred solution of 11.1 g. (50 millimol) dodecahydro 5,9-methano-10-methylbenzocycloocten-4a,ll-diol in 125 cc. dry benzene is added 8.3 g. (150 millimol) methyl isocyanate in 125 cc. dry benzene over about 5 minutes. The resulting solution is refluxed for l824 hours and then the solvent is stripped. The solid is triturated with 500 cc. hot petroleum ether and the insolubles filtered. This solid is twice recrystallized from 50% aqueous EtOH to give 10 g. of dodecahydro- 5,9-methano 10 methylbenzocycloocten-4a,11-diol(2-5- dimethylallophinate) as a colorless solid, melting at 147- 149 C. IR (Nujol) 3350, 3300, 1715, 1660, 1530, 1270, 1200, 1160, 1010; NMR (CDCl;,) 0.9 and 1.0 (C-CH 2.6 (tert.OH), 2.8 and 2.9 (NHC 3), 3.2 (N-CH 8.5 (NH).

Analysis-Called. for C H N O C, 63.88; H, 8.93; N, 8.28. Found. C, 64.12; H, 9.07; N, 8.43.

EXAMPLE 3 Dodecahydro-5,9-methanol O-methylbenzocycloocten- 4a,11-diol 1 l-carbamate To a suspension of 2.25 g. (10 mM.) dodecahydro-5,9- methano-lO-methylbenzocycloocten-4a,1l-diol and 1.30 g. sodium isocyanate in 20 ml. of dry benzene, is added a solution of 1.55 ml. trifluoroacetic acid in 5 ml. of dry benzene and the suspension is stirred at room temperature overnight. Ten milliliters of water are added and the resulting precipitate is filtered. The solid is recrystallized from equal parts of abs. ethanol and anhyd. ether, to give 1.0 g. (37.5%) of the desired dodecahydro-5,9- methano 10 methylbenzocycloocten-4a,l l-diol ll-carbamate, melting at 263-265 C. IR (Nujol) 3500, 3350, 1705, 1600, 1405, 1050, 960, 940.

Analysis.-Calcd. for C H NO C, 67.38; H, 9.43; N, 5.24. Found: C, 67.48; H, 9.49; N, 5.44.

EXAMPLE 4 l,2,3,4,4a (or 10) 5,6,7,8,9-decahydro-5,9-methano-10- methylbenzocycloocten- 1 l-ol carb amate Gaseous HCl is bubbled through a suspension of 2.24 g. (10 mM.) dodecahydro-S ,9 methano-lO-methylbenzocyc1oocten-4a,11-diol and 1.30 g. (20 mM.) dried sodium isocyanate in 25 ml. dry CHCl for 15 min. then allowed to stir at room temperature overnight. Tenmilliliters of H 0 are added and the reaction mixture is extracted with ether. On removal of the solvent, the residue is recrystallized from acetonitrile to give 11 which melts at 146 C. IR (mull) 3500, 3220, 1710, 1590, 1400, 1320, 1125, 1030. The NMR indicates that this compound is a mixture of double bond isomers.

Analysis.Calcd. for C H NO C, 72.25; H, 9.30; N, 5.62. Found: C, 72.38; H, 9.40; N, 5.40.

EXAMPLE 5 Dodecahydro-5,9-methano-10-methylbenzocycloocten- 4a,1 l-diol l 1- 3-pyridine carbamate) To a suspension of 1.20 g. (10 mM.) 3-pyridyl isocyanate in 25 ml. dry benzene is added 2.24 g. (10 mM.) dodecahydro-5,9-methano l0 methylbenzocycloocten- 4a,1l-diol in 50 ml. dry benzene. The resulting suspension is refluxed for 1 hr. and the solvent is removed. The resulting solid is recrystallized from cyclohexane to give 1.7 g. (50%) of the product, melting at 157 C. IR (mull) 3600, 3200, 1730, 1600, 1550, 1425, 1410, 1370, 1215, 1050, 1020.

Analysis.-Calcd. for C H N O C, 69.74; H, 8.19; N, 8.13. Found: C, 70.01, H, 8.25; N, 7.99.

EXAMPLE 6 l l-amino-dodecahydro-S,9-methano-10-methylbenzocyclooctene hydrochloride To a solution of 11.1 g. (50 mM.) of dodecahydro- 5,9-methano 10 methylbenzocycloocten-4a-ol-ll-one in 7.9 ml. of formarnide heated to C. is added 6.4 ml. (125 mM.) of formic acid in five portions and the reaction mixture is stirred for 2 hrs. after each addition. The mixture is cooled and 7.5 ml. of cone. HCl is added and the temperature again raised to 170 C. When the excess reagents have boiled away, there remains a solid which when recrystallized from abs. ethanol and anhydrous thelc'ngives 6.09 g. (50%) of the product melting at 270 Analysis.-Calcd. for C H N-HCI: C, 68.97; H, 10.75; N, 5.74; Cl, 14.54. Found: C, 69.00; H, 11.03; N, 5.61; Cl, 14.50.

The free base is liberated by extraction from a basic aqueous solution with ether and boiled between 130-150 C. at 0.1 mm.

EXAMPLE 7 1- (dodecahydro-5,9-methano-IO-methylbenzocycloocten-l l-yl -3 -methylurea To a stirred solution of 5.2 g. (25 mM.) of ll-aminododecahydro-5,9-methano-10-methylbenzocyclooctene in 125 ml. dry C H is added a solution of 1.38 g. (25 mM.) of methyl isocyanate in 67 ml. dry C H dropwise over 30 minutes. The resulting suspension is stirred at R.T. overnight then refluxed for five hrs. The solid filtered and recrystallized from carbon tetrachloride to give one isomer of the desired compound melting at 189-192 C. (Isomer A). When the filtrate from the reaction is evaporated to dryness and the resulting solid recrystallized from car bon tetrachloride, another isomer of the desired compound is obtained melting at 194196 C. (Isomer B). IR (mull) Isomer A: 3250, 1655, 1535, 1410, 1270, 1165, 1115. IR (mull) Isomer B: 3250, 1660, 1540, 1410, 1270, 1160, 1110.

AnaIysis.-Calcd. for C H N O: C, 72.68; H, 10.67; N, 10.60. Found (isomer A): C, 72.98; H, 10.70; N, 10.36. Found (isomer B): C, 72.46; H, 10.67; N, 10.26.

EXAMPLE 8 1- (dodecahydro-S,9-methano--methylbenzocycloocten-l1-yl)-3-(3-pyridyl)urea A suspension of 10.35 g. (30 mM.) of ll-aminododecahydro-5,9-methano-10-methylbenzocyclooctene and 6.0 g. (30 mM.) 3-pyridy1 isocyanate in 375 m1. dry benzene was refluxed for 2 hrs. The resulting solution left at RT. overnight. The solid filtered and recrystallized from C H to give 5.1 g. (52%) of an isomer of the desired product melting at 201-207 C. (isomer A). The filtrate was evaporated to dryness and the resulting oil recrystallized from C H containing an equal volume of C H to give 3.1 g. (32%) of another isomer of the desired compound melting at 153159 C. (isomer B). IR (mull) (isomer A): 3300, 1660, 1590, 1515, 1400, 1230, 760. IR (mull) (isomer B): 3200, 1630, 1590, 1520, 1400, 1370, 1340, 1320, 1300, 1225, 1180, 795, 745, 705.

Analysis.-Calcd. for C H N O: C, 73.35; H, 8.93; N, 12.83. Found (isomer A): C, 73.45; H, 8.95; N, 12.62. Found (isomer B): C, 73.20; H, 9.07; N, 12.78.

References Cited Julia et al., Chem. Abstracts, vol. 52, par. 13620(c) Julia et al., Chem. Abstracts, vol. 54, Far. 1643116433 (1960).

Barbules-cu, Chem. Abstracts, vol. 57, Par. 8455d (1962).

Camps et al., Chem. Abstracts, vol. 57 8621c (1962). Chem. Abstracts Subject Index S-Z, page 1536 (July, December 1962.

HENRY R. JILES, Primary Examiner ALAN L. ROTMAN, Assistant Examiner US. Cl. X.R. 

